Abstract
Systemic administration of local anesthetics has beneficial perioperative properties and an anesthetic-sparing and antiarrhythmic effect, although the detailed mechanisms of these actions remain unclear. In the present study, we investigated effects of a local anesthetic, lidocaine, on HCN channels that contribute to the pacemaker currents in rhythmically oscillating cells of the heart and brain. Voltage clamp recordings were employed to examine properties of cloned HCN subunit currents expressed in Xenopus oocytes and HEK293 cells under control condition and lidocaine administration. Lidocaine inhibited HCN1, HCN2, HCN1-HCN2 and HCN4 channel currents at 100 μM in both oocytes and/or HEK293 cells; it caused a decrease in both tonic and maximal current (~30 to 50% inhibition) and slowed current activation kinetics for all subunits. In addition, lidocaine evoked a hyperpolarizing shift in half-activation voltage (ΔV&frac12; of ~-10 to -14 mV), but only for HCN1 and HCN1-HCN2 channels. By fitting concentration-response data to logistic functions we estimated half-maximal (EC(50)) concentrations of lidocaine of ~30 to 40 μM for the shift in V&frac12; observed with HCN1 and HCN1-HCN2; for inhibition of current amplitude, calculated EC50 values were ~50 to 70 μM for HCN1, HCN2 and HCN1-HCN2 channels. A lidocaine metabolite, monoethylglycinexylidide (100 μM) had similar inhibitory actions on HCN channels. These results indicate that lidocaine potently inhibits HCN channel subunits in dose-dependent manner over a concentration range relevant for systemic application. The ability of local anesthetics to modulate I(h) in central neurons may contribute to CNS depression while effects on I(f) in cardiac pacemaker cells may contribute to the antiarrhythmic and/or cardiovascular toxic action.